Unlike other tissue which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which was early characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normally, high glutamate concentrations are maintained inside cells of the CNS by energy-dependent transport systems, but high concentrations are not allowed in the extracellular compartment where glutamate can exert excitotoxic action at excitatory synaptic receptors. Under low energy conditions such as hypoglycemia, hypoxia or ischemia, cells release glutamate and, because of the energy deficiency, the transport systems are unable to move glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia--Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate receptors, also known as excitatory amino acid (EAA) receptors, are of three types, each being named after the EAA glutamate analogue which selectively excites them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS). Glutamate is believed to be a mixed (broad spectrum) agonist capable of binding to and exciting all three EAA receptor types.
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia which occurs in conditions such as stroke, cardiac arrest or perinatal asphyxia.
Phencyclidine (PCP) and the PCP-like compound ketamine have been found to reduce selectively the excitatory effects of NMDA as compared to KA and QUIS [Anis, N.A. et al, "The Dissociative Anaesthetics, Ketamine and Phencyclidine, Selectively Reduce Excitation of Central Mammalian Neurones by N-Methyl-Aspartate", Br. J. Pharmacol., 79, 565 (1983)]. Blocking of NMA neurotoxicity by PCP and ketamine has been demonstrated [J. W. Olney et al., "The Anti-Excitotoxic Effects of Certain Anesthetics, Analgesics and SedativeHypnotics," Neuroscience Letters68, 29-34 (1986)].
A correlation has been found between the PCP binding effects of some PCP-derivative stereoisomers and NMDA antagonism. For example, the stereoselective effects of cis-N-(1-phenyl-4-methylcyclohexyl)piperidine and (+)-1-(1-phenylcyclohexyl)-3-methylpiperidine [(+)-PCMP] over each of their corresponding isomer counterparts in reducing the excitatory action of NMDA have been confirmed in binding and behavioral data [S. D. Berry et al, "Stereoselective Effects of Two Phencyclidine Derivatives on N-Methylaspartate Excitation of Spinal Neurones in the Cat and Rat", Eur. J. Pharm., 96, 261-267 (1983)]. Also, the compound (+)-PCMP has been found to be a potent inhibitor of the specific binding of [.sup.3 H]PCP to rat cerebral cortical membranes [M. E. Goldman et al, "Differentiation of [.sup.3 H]Phencyclidine and (+)-[.sup.3 H]SKF-10,047 Binding Sites in Rat Cerebral Cortex", FEBS Lett., 170, 333-336 (1985)]. It has also been shown that PCP and NMA receptors are co-localized throughout much of the mammalian forebrain [W. Maragos et al, "High Correlation between the Localization of [.sup.3 H]TCP Binding and NMDA Receptors", Eur. J. Pharmacol., 123, 173-174 (1986)].
The compound MK-801 {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate)} has been found to be a potent, selective non-competitive antagonist of the N-methyl-D-aspartate receptor site [E. H. F. Wong et al, "The Anticonvulsant MK-801 Is A Potent N-Methyl-D-Aspartate Antagonist", Proc. Nat'l. Acad. Sci U.S.A., Vol. 83, pp. 7104-7108 (Sept. (1986)].
Well-known competitive NMA antagonists, such as D-.alpha.-amino-5-phosphonopentanoate, are capable of effectively blocking the excitotoxic effects of NMA. But such compounds show little therapeutic promise in treatment or prevention of ischemic brain damage because these compounds do not penetrate the blood-brain barrier.
Phenothiazinealkaneamines and derivatives have been described for various pharmaceutical purposes. For Example, ethopropazine is an anti-cholinergic useful in treatment of Parkinsonism [L. S. Goodman et al, "The Pharmacological Basis of Therapeutics, 5th Edn. Macmillan (1975)]. The compound 2-propionyl-10-[2-(dimethylaminopropyl]phenothiazine is mentioned in a study of the interaction of certain tranquilizers and antihistamines on bacterial cells [A. M. Shibl et al, J. Pharm. Sci., 73(b), 841-843 (1984)]. The compound N,N-diethyl-3-methyl-10H-phenothiazine-10-ethanamine monohydrochloride is mentioned in a study of phenothazine derivatives as inhibitors of gastric acid secretion [A. Canas-Rodriguiz et al, An. Quim., Ser. C., 80 (1), 39-41 (1984)]. The compound 1-[10-[2-(dimethylaminoethyl]-10H-phenothiazin-2-yl]ethanone is mentioned in a study of derivatives of 2-phenothiazin-2'-ylcinchoninic acid having potential analgesic-antiinflammatory activity [F. Savelli, Chim. Ind. (Milan), 59(4), 300 (1977)]. The compound 2-chloro-N,N-diethyl-10H-phenothiazine-10-ethanamine monohydrochloride is mentioned in a study of the correlation between neuroleptic activity and the anticholinesterase property of some phenothiazine derivatives [J. Legheand et al, Ann. Pharm. Fr., 31(9-10), 613-622 (1973)]. The compound dimethothiazine methanesulfonate is mentioned for prevention of death from ulcer and shock in Japanese Patent Application Kokai 56/26817 (March 1981). The compound 10-[2,3-bis(dimethylamino)propyl]phenothiazine is mentioned in a study of the effect of neuroleptics, tranquilizers, narcotics, antidepressants and anticonvulsive drugs on the alteration of mouse behavior caused by acetaldehyde [L. M. Andronova et al, Drug Alcohol Depend., 8(2), 85-92 (1981)]. The compound 10-[2-(dimethylaminopropyl] -N,N-dimethyl-10H-phenothiazine-2-sulfonamide methanesulfonate is mentioned in a study of the effects of some drugs on the rigidity of the cat due to ischemic or intercollicular decerebration [D. R. Maxwell et al, Neuropharmacology, 11, (6), 849 -855 (1972)].